Chrystalline duloxetine hydrochloride

ABSTRACT

Crystalline duloxetine hydrochloride, compositions containing the same and methods for the production thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from Great Britain Application NumberGB 0612508.2, filed 23 Jun. 2006.

FIELD OF THE INVENTION

The present invention relates to crystalline duloxetine hydrochloride,to compositions containing the same and to methods for the formationthereof.

BACKGROUND OF THE INVENTION

Duloxetine hydrochloride is a potent dual reuptake inhibitor ofserotonin and norepinephrine possessing comparable affinities in bindingto serotonin and norepinephrine transport sites. Duloxetinehydrochloride has, therefore, been implicated in the treatment ofvarious diseases related to these effects. For example, duloxetinehydrochloride is the active ingredient of the antidepressant drugCymbalta®. It is also used to target pain related to diabetic neuropathyand stress urinary incontinence.

Preparation of duloxetine hydrochloride has been disclosed elsewhere,for example in U.S. Pat. No. 5,023,269. Crystalline forms of the freebase of duloxetine and their preparation have been reported inWO2005/108386. The amorphous form of duloxetine hydrochloride salttogether with its preparation has been reported in WO2005/019199.

There is no generally applicable method for preparing a crystalline formof an amorphous drug. For example, it is impossible to know withoutexperimentation whether any crystalline form of a given compound exists.Even once it has been found that a drug can be crystallised, extensiveexperimentation is usually required before a repeatable and quantifiableprocess is identified from which the crystalline form can be isolated.In this respect, several independently variable conditions, such as thenature of solvent, concentration of solvent and temperature, must becorrectly identified in order to elucidate a suitable process. Indeed,to date, there have been no reports describing isolation or productionof crystalline duloxetine hydrochloride.

It is, therefore, an object of the present invention to providecrystalline forms of duloxetine hydrochloride together with methods forthe production thereof.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention, there is providedcrystalline duloxetine hydrochloride.

According to another aspect of the present invention, there is providedcrystalline duloxetine hydrochloride which exhibits an X-ray diffractionpattern comprising peaks expressed in degrees two-theta at approximately11.99±0.2, 14.78±0.2, 21.44±0.2, 22.16±0.2, 23.12±0.2 and 24.12±0.2. Thedegree of error is preferably ±0.1.

According to a further aspect of the present invention, there isprovided crystalline duloxetine hydrochloride which exhibits an X-raydiffraction pattern comprising peaks expressed in degrees two-theta atapproximately 11.02±0.2, 11.99±0.2, 13.94±0.2, 14.78±0.2, 16.19±0.2,16.87±0.2, 18.0±0.2, 18.8±0.2, 19.77±0.2, 20.84±0.2, 21.44±0.2,22.16±0.2, 23.12±0.2, 24.12±0.2, 26.34±0.2, 26.76±0.2, 27.0±0.2,27.45±0.2, 29.24±0.2, 29.58±0.2, 29.92±0.2, 30.4±0.2, 32.2±0.2,32.82±0.2 and 34.17±0.2. The degree of error is preferably ±0.1.

There is also provided by the present invention, crystalline duloxetinehydrochloride which exhibits an X-ray diffraction pattern substantiallythe same as shown in FIG. 1.

Preferably, the crystalline duloxetine hydrochloride has a purity of atleast 95%, more preferably at least 98%.

According to a further aspect of the present invention, there isprovided a method for the preparation of crystalline duloxetinehydrochloride, the method comprising:

-   -   (a) dissolving duloxetine in a first organic solvent to form a        first solution;    -   (b) adding the first solution to a second organic solvent        solution comprising HCl to form a second solution;    -   (c) allowing duloxetine hydrochloride to crystallize out from        the solution; and    -   (d) collecting the crystallized duloxetine hydrochloride.

Preferably, the first organic solvent is an aromatic hydrocarbon, morepreferably toluene.

In preferred embodiments, the second organic solvent is an alcohol, morepreferably a straight or branched C₁ to C₆ alcohol, further preferablyethanol.

Preferably, the duloxetine is dissolved in the first organic solvent ina ratio of about 40 ml first organic solvent for about every 3 g ofduloxetine.

In preferred aspects, the second organic solvent comprises about 20%HCl.

It is also preferred that the first solution is added to the secondorganic solvent at around 0° C. The first solution is preferably addedto the second organic solvent with stirring.

In order to maximize crystallization, the duloxetine hydrochloride maybe allowed to crystallize out from the solution during a period ofcooling at around 0° C. to around 10° C. Preferably, the duloxetinehydrochloride is allowed to crystallize out from the solution during aperiod of about 10 hours.

Preferably, the crystallized duloxetine hydrochloride is collected byfiltration. The collected crystallized duloxetine hydrochloride ispreferably washed and then dried.

In preferred embodiments, the collected crystallized duloxetinehydrochloride is washed with an aromatic hydrocarbon, more preferablytoluene.

Preferably, the collected crystalline duloxetine hydrochloride is driedunder vacuum.

Preferably, the method comprising the following additional steps for thepreparation of duloxetine for use in step (a):

(i) placing duloxetine oxalate into a solution of a third organicsolvent and water;

(ii) adding aqueous ammonia solution for dissolving the duloxetineoxalate;

(iii) isolating a separated organic layer;

(iv) washing the organic layer with saturated brine;

(v) drying the organic layer; and

(vi) removing the solvents from the organic layer.

Preferably, the third organic solvent is a C₁ to C₆ ester, morepreferably ethyl acetate.

The duloxetine oxalate is preferably placed into a solution of the thirdorganic solvent and water at a ratio of about 300 ml third organicsolvent and water solution for about every 39 g of duloxetine oxalate.

Preferably, the solution of a third organic solvent and water containsabout 1 ml third organic solvent for about every 1 ml water.

The aqueous ammonia is preferably added under stirring.

Preferably, an aqueous layer is isolated and then washed with the thirdorganic solvent.

According to a further aspect of the present invention, there isprovided crystalline duloxetine hydrochloride prepared by any of themethods above.

Preferably, the crystalline duloxetine hydrochloride has a purity of atleast 95%, more preferably at least 98%.

Accordingly, the present invention describes a novel crystalline form ofduloxetine hydrochloride and a process to prepare it.

It is anticipated that the crystalline form of duloxetine hydrochloridedisclosed herein will be useful in the treatment of a variety ofdiseases which are prevented, ameliorated or eliminated by theadministration of a serotonin and/or norepinephrine reuptake inhibitor.Examples of such diseases include depression, pain related to diabeticneuropathy and stress urinary incontinence, obesity, alcoholism, loss ofmemory, anxiety and smoking.

According to another aspect of the present invention, there is thereforeprovided a pharmaceutical composition comprising crystalline duloxetinehydrochloride as described herein.

According to a further aspect, there is provided a composition fortreating a disease which is prevented, ameliorated or eliminated by theadministration of a serotonin and/or norepinephrine reuptake inhibitor,the composition comprising crystalline duloxetine hydrochloride asdescribed herein.

Preferably, the disease is selected from depression, pain related todiabetic neuropathy and stress urinary incontinence, obesity,alcoholism, loss of memory, anxiety and smoking.

There is also provided a method of treating a disease which isprevented, ameliorated or eliminated by the administration of aserotonin and/or norepinephrine reuptake inhibitor, the methodcomprising administering to a patient a therapeutically effective amountof crystalline duloxetine hydrochloride as described herein, or of thepharmaceutical composition as described herein.

Preferably, the disease is selected from depression, pain related todiabetic neuropathy and stress urinary incontinence, obesity,alcoholism, loss of memory, anxiety and smoking.

By a therapeutically effective amount, it is meant an amount which iscapable of preventing, ameliorating or eliminating the diseasesmentioned herein.

The crystalline duloxetine hydrochloride can be mixed with a carrier,diluent or excipient therefor, all of which are well known in the art.For example, suitable carriers may include pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols, ointments, soft and hard gelatine capsules, suppositories,sterile injectable solutions and sterile packaged powders.

There are many advantages to providing a crystalline form of duloxetinehydrochloride compared to an amorphous form. A crystalline form of thedrug can be easily purified by crystallisation and recrystallisation.Compared to other methods of purification, it is also cheaper and moreconvenient to perform crystallisation on a large scale. Furthermore, acrystalline form may be more stable than an amorphous form.

BRIEF DESCRIPTION OF THE DRAWINGS

An example of the present invention will now be described in detail withreference to the accompanying figures.

FIG. 1 shows the X-ray powder diffraction (XRD) spectrum for thecrystalline form of the present invention.

FIG. 2 shows Thermogravimetric Analysis (TGA) and Differential ThermalAnalysis (DTA) thermograms for the crystalline form of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

Duloxetine oxalate salt was initially prepared following the proceduregiven in EP273658 (corresponding to U.S. Pat. Nos. 5,023,269 and4,956,388, each hereby incorporated by reference). Duloxetine was thenfreed from the oxalic acid and converted directly to its hydrochloridesalt by the introduction of hydrochloride in organic solvent.

The isolated crystalline duloxetine hydrochloride was fullycharacterized by Differential Scanning Calorimetry (DSC), solidcarbon-13 NMR and X-ray powder diffraction.

Crystallization

EXAMPLE 1 Free Duloxetine Preparation

Duloxetine oxalate (38.7 g) was placed into 300 ml of an ethylacetate/water (1:1) mixture. Aqueous ammonium solution was added todissolve the solid completely under stirring. The separated aqueouslayer was washed with ethyl acetate twice. The combined organic solutionwas then washed with saturated brine, and dried with anhydrous sodiumsulphate. The free duloxetine (26 g) was obtained as an oil by removingthe solvents from the filtrate solution.

Crystallization of Duloxetine Hydrochloride:

The free oily duloxetine (3 g) was added to toluene (40 ml), then anethanol solution (2 ml) containing 20% HCl was added at 0° C. Theresultant solution was then stirred for an extra half hour and kept at0-10° C. for 10 hours. The product crystallized out and was collected byfiltration, washed with more toluene and dried (1.7 g, 53% yield, m.p.154-158° C.). Its purity was determined to be 98.9% by HPLC, and itsoptical purity was 99.4% (chiral column HPLC). The DTA result shown m.p.was 169.2° C. The crystalline form, designated as Form II, was thusobtained. TABLE 1 The XRD spectrum for the crystalline form obtainedaccording to Example 1. 2theta (degree) I/I₀ d(A) 11.021 16 8.021 11.99354 7.373 13.936 18 6.349 14.780 73 5.988 16.192 32 5.469 16.868 15 5.25117.997 25 4.924 18.792 30 4.718 19.765 16 4.488 20.842 31 4.258 21.444100 4.140 22.159 58 4.008 23.120 84 3.843 24.122 71 3.686 26.341 243.380 26.760 19 3.328 27.000 31 3.299 27.448 12 3.246 29.240 19 3.05129.580 19 3.017 29.920 21 2.983 30.398 12 2.938 32.200 14 2.777 32.82010 2.726 34.165 14 2.622

TABLE 2 TGA/DTA parameters Detector DTG-60H Sample Weight 7.698 mgTemperature Rate 10° C. Hold Temperature 300° C. Hold Time 0 min

1. A method for the preparation of crystalline duloxetine hydrochloride,the method comprising: (a) dissolving duloxetine in a first organicsolvent to form a first solution; (b) adding the first solution to asecond organic solvent comprising HCl to form a second solution; (c)allowing duloxetine hydrochloride to crystallize out from the solution;and (d) collecting the crystallized duloxetine hydrochloride, whereinthe first organic solvent is an aromatic hydrocarbon.
 2. The method ofclaim 1, wherein the first organic solvent is toluene.
 3. The method ofclaim 1, wherein the second organic solvent is an alcohol.
 4. The methodof claim 3, wherein the second organic solvent is ethanol.
 5. The methodof claim 1, wherein the duloxetine is dissolved in the first organicsolvent in a ratio of about 40 ml first organic solvent for about every3 g of duloxetine.
 6. The method of claim 1, wherein the second organicsolvent comprises about 20% HCl.
 7. The method of claim 1, wherein thefirst solution is added to the second organic solvent at around 0° C. 8.The method of claim 1, wherein the first solution is added to the secondorganic solvent with stirring.
 9. The method of claim 1, wherein theduloxetine hydrochloride is allowed to crystallize out from the solutionduring a period of cooling at around 0° C. to around 10° C.
 10. Themethod of claim 1, wherein the duloxetine hydrochloride is allowed tocrystallize out from the solution during a period of about 10 hours. 11.The method of claim 1, wherein the crystallized duloxetine hydrochlorideis collected by filtration.
 12. The method of claim 1, wherein thecollected crystallized duloxetine hydrochloride is washed and thendried.
 13. The method of claim 12, wherein the collected crystallizedduloxetine hydrochloride is washed with an aromatic hydrocarbon.
 14. Themethod of claim 13, wherein the collected crystallized duloxetinehydrochloride is washed with toluene.
 15. The method of claim 1,comprising the following additional steps for the preparation ofduloxetine for use in step (a): (i) placing duloxetine oxalate into asolution of a third organic solvent and water; (ii) adding aqueousammonia solution for dissolving the duloxetine oxalate; (iii) isolatinga separated organic layer; (iv) washing the organic layer with saturatedbrine; (v) drying the organic layer; and (vi) removing the solvents fromthe organic layer.
 16. The method of claim 15, wherein the third organicsolvent is a C₁ to C₆ ester.
 17. The method of claim 16, wherein thethird organic solvent is ethyl acetate.
 18. The method of claim 15,wherein duloxetine oxalate is placed into a solution of the thirdorganic solvent and water at a ratio of about 300 ml third organicsolvent and water solution for about every 39 g of duloxetine oxalate.19. The method of claim 15, wherein the solution of a third organicsolvent and water contains about 1 ml third organic solvent for aboutevery 1 ml water.
 20. The method of claim 15, wherein the aqueousammonia is added under stirring.
 21. The method of claim 15, wherein anisolated aqueous layer is washed with the third organic solvent.
 22. Themethod of claim 15, wherein the organic layer is dried with anhydroussodium sulphate.
 23. Crystalline duloxetine hydrochloride prepared bythe method of claim
 1. 24. Crystalline duloxetine hydrochloride whichexhibits an X-ray diffraction pattern comprising peaks expressed indegrees two-theta at approximately 11.99±0.2, 14.78±0.2, 21.44±0.2,22.16±0.2, 23.12±0.2 and 24.12±0.2.
 25. The crystalline duloxetinehydrochloride of claim 24, which exhibits an X-ray diffraction patterncomprising peaks expressed in degrees two-theta at approximately11.02±0.2, 11.99±0.2, 13.94±0.2, 14.78±0.2, 16.19±0.2, 16.87±0.2,18.0±0.2, 18.8±0.2, 19.77±0.2, 20.84±0.2, 21.44±0.2, 22.16±0.2,23.12±0.2, 24.12±0.2, 26.34±0.2, 26.76±0.2, 27.0±0.2, 27.45±0.2,29.24±0.2, 29.58±0.2, 29.92±0.2, 30.4±0.2, 32.2±0.2, 32.82±0.2 and34.17±0.2.
 26. The crystalline duloxetine hydrochloride of claim 25,which exhibits an X-ray diffraction pattern substantially the same asshown in FIG.
 1. 27. The crystalline duloxetine hydrochloride of claim24, which exhibits a TGA thermogram substantially the same as shown inFIG.
 2. 28. The crystalline duloxetine hydrochloride of claim 27, whichexhibits a DTA thermogram substantially the same as shown in FIG.
 2. 29.The crystalline duloxetine hydrochloride of claim 25, which has a purityof at least 95%.
 30. The crystalline duloxetine hydrochloride of claim29, which has a purity of at least 98%.
 31. The crystalline duloxetinehydrochloride of claim 25, which has an optical purity of at least 95%.32. The crystalline duloxetine hydrochloride of claim 31, which has anoptical purity of at least 98%.
 33. The crystalline duloxetinehydrochloride of claim 25, defined as Form II.
 34. A pharmaceuticalcomposition comprising the crystalline duloxetine hydrochloride of claim25.
 35. A composition for treating a disease which is prevented,ameliorated or eliminated by the administration of a serotonin reuptakeinhibitor, a norepinephrine reuptake inhibitor, or a serotonin andnorepinephrine reuptake inhibitor, the composition comprising thecrystalline duloxetine hydrochloride of claim
 25. 36. The composition ofclaim 35, wherein the disease is selected from depression, pain relatedto diabetic neuropathy and stress urinary incontinence, obesity,alcoholism, loss of memory, anxiety and smoking.
 37. A method oftreating a disease which is prevented, ameliorated or eliminated by theadministration of a serotonin reuptake inhibitor, a norepinephrinereuptake inhibitor, or a serotonin and norepinephrine reuptakeinhibitor, the method comprising administering to a patient atherapeutically effective amount of the crystalline duloxetinehydrochloride of claim
 25. 38. The method of claim 37, wherein thedisease is selected from depression, pain related to diabetic neuropathyand stress urinary incontinence, obesity, alcoholism, loss of memory,anxiety and smoking.